With unexpected discoveries on a protein highly expressed in adipose tissue, scientists at Scripps Research have opened the door to new critical knowledge on obesity and metabolism. Their discovery, which appears on November 20 in the journal Nature, could lead to new approaches to fight obesity and potentially many other diseases.
The signaling protein, known as PGRMC2, has not been widely studied in the past. Abbreviation for "component 2 of the progesterone receptor membrane", it had been detected in the uterus, liver and several parts of the body. But Enrique Saez's laboratory, PhD, found that it was most abundant in adipose tissue - especially in brown fat, which turns food into heat to maintain body temperature - and was interested in its function there.
An important role: the Heme travel guide
The team built on their recent discovery that PGRMC2 binds to and releases an essential molecule called heme. Recently honored for its role in providing flavor to the herbal Impossible Burger, heme plays a much more important role in the body. The iron-containing molecule travels inside cells to enable crucial life processes such as cell respiration, cell proliferation, cell death and circadian rhythms.
Using biochemical techniques and advanced cell testing, Saez and his team discovered that PGRMC2 is a heme "chaperone", encapsulating the molecule and transporting it from the mitochondria of the cell, where the heme is created, to 'at the core, where it helps carry out important functions. Without a protective hood, the heme would react with - and destroy - everything in its path.
"The importance of heme for many cellular processes has been known for a long time," says Saez, associate professor in the Department of Molecular Medicine. "But we also knew that heme is toxic to the cellular materials around it and would need some sort of shuttle pathway. Until now there were many hypotheses, but the proteins that trafficked the heme had not been identified. "
An innovative approach to obesity?
Through studies involving mice, scientists have established PGRMC2 as the first intracellular haem chaperone to be described in mammals. However, they did not stop there; they tried to find out what is going on in the body if this protein does not exist to transport heme.
And this is how they made their next big discovery: without PGRMC2 present in their adipose tissue, mice that were fed a diet high in fat became glucose intolerant and insulin insensitive - symptoms characteristic of diabetes and other metabolic diseases. In contrast, obese diabetic mice who were treated with a drug to activate the PGRMC2 function showed substantial improvement in symptoms associated with diabetes.
"We have seen mice improve, become more glucose tolerant and less resistant to insulin," says Saez. "Our results suggest that modulating PGRMC2 activity in adipose tissue may be a useful pharmacological approach to reverse some of the serious health effects of obesity."
The team also assessed how the protein changes other functions of brown and white fats, says lead study author Andrea Galmozzi, PhD. "The first surprise discovery was that the brown fat looked white," he says.
Brown fat, which is normally the highest in heme content, is often considered the "good fat". One of its key roles is to generate heat to maintain body temperature. In mice unable to produce PGRMC2 in their adipose tissue, temperatures dropped rapidly when placed in a cold environment.
"Even if their brains sent the right signals to turn on the heat, the mice could not defend their body temperature," says Galmozzi. "Without heme, you get mitochondrial dysfunction and the cell has no way to burn energy to generate heat."
Saez thinks it is possible that activating the heme chaperone in other organs - including the liver, where a large amount of heme is produced - could help ease the effects of other metabolic disorders such than nonalcoholic steatohepatitis (NASH), which is a major cause of liver transplantation today.
"We are curious to know if this protein plays the same role in other tissues where we observe heme defects which lead to diseases", explains Saez.
Andrea Galmozzi, Bernard P. Kok, Arthur S. Kim, J. Rafael Montenegro-Burke, Jae Y. Lee, Roberto Spreafico, Sarah Mosure, Verena Albert, Rigo Cintron-Colon, Cristina Godio, William R. Webb, Bruno Conti, Laura A. Solt, Douglas Kojetin, Christopher G. Parker, John J. Peluso, James K. Pru, Gary Siuzdak, Benjamin F. Cravatt, Enrique Saez. PGRMC2 is an intracellular haem chaperone critical for adipocyte function. Nature, 2019; DOI: 10.1038/s41586-019-1774-2